A large clinical trial of an AIDS vaccine has, for the first time, yielded positive results. But researchers immediately questioned the relevance of the data, which indicated that the vaccine offered only modest protection against infection by HIV.

The controversial trial, conducted with more than 16,000 volunteers in Thailand over the past 6 years, tested the effectiveness of two AIDS vaccines used together as a one-two punch. Researchers randomly assigned an equal number of participants who were at average risk of becoming infected by HIV to receive either the two vaccines or a saline placebo. At the end of the study in June, 51 of the vaccinated people had become infected within 3 years of receiving their last shot, compared with 74 people in the placebo group. The p value, which indicates whether results are due to chance, was less than 0.039, just below the widely accepted but arbitrary “significance” cutoff of 0.05. Surprisingly, the vaccine did not appear to suppress levels of the virus in the 51 people who became infected. No serious adverse events were seen in either group.

Many AIDS vaccine researchers had predicted that the study would fail, and its sponsors are thrilled by the efficacy, marginal though it may be. “Although the level of protection was modest, we think the study is a major scientific advance,” said Colonel Jerome Kim, HIV vaccines product manager for the U.S. Army, which collaborated with the Thai Ministry of Health to conduct the efficacy trial. “We were all pretty energized by the results.” The U.S. military and Thai officials will announce the results of the trial, the largest ever held of an AIDS vaccine (see table on other AIDS vaccine trials after the jump), at press conferences today in Thailand and the United States.

Several longtime critics of the study, which cost $105 million, were dumbfounded—and circumspect—when they learned the results.

“Wow. Wow,” said AIDS vaccine researcher Ronald Desrosiers, head of the New England Primate Research Center in Southborough, Massachusetts. “Looking at the numbers, it’s underwhelming to me. But I want to sit tight and get a bunch of people to do analyses and see whether the protective effect holds up under greater scrutiny.” Dennis Burton, an immunologist at the Scripps Research Institute in San Diego, California, had a similar reaction. “It’s very early days,” said Burton. “People should be enormously cautious now.” In an editorial published in Science[2] shortly after the trial began (16 January 2004, p. 316), Desrosiers, Burton, and 20 other prominent AIDS researchers argued that the study never should have been launched.

Skepticism about the study stemmed from previous lackluster results of the vaccines, tested separately and together, in smaller clinical trials. In the just-finished trial, vaccinated individuals first received “priming” from a preparation, made by Sanofi Pasteur based in Lyon, France, that contained a canarypox virus that researchers had engineered to contain HIV genes. A “booster” shot contained a recombinant form of HIV’s surface protein, gp120, made by VaxGen, a company in South San Francisco, California. VaxGen sold the rights to develop the product to Global Solutions for Infectious Diseases after the product failed in large efficacy trials when tested alone[3]. Both vaccines were based on HIV strains that are circulating in Thailand.

Even though the data are positive, U.S. military researchers stress that many discussions must still take place before anyone decides to use vaccines with such modest efficacy. Still, Colonel Nelson Michael, director of the U.S. Military HIV Research Program, said he hopes the results will help researchers finally untangle which immune responses correlate with protection, and then build on that information to design more effective vaccines. “These results at least are telling us that walking down this road is worthwhile,” said Michael. “From a scientific viewpoint, I pray this will begin to inform our arguments. So much of what people have said in absence of a clinical hit like this is theology. We finally have an argument that will be suffused with data rather than theories.”

Michael and his colleagues plan to present the data more fully at an AIDS vaccine conference in Paris[4] on 19–22 October. “This is certainly going to stir up the field,” Desrosiers said.